Hereditary sensory neuropathies (HSNs) form part of the inherited peripheral neuropathies which are generally subdivided into three categories, reflecting the selective or predominant involvement of the motor or sensory peripheral nervous system. The most common variants are the hereditary motor and sensory neuropathies (HMSNs), also called Charcot-Marie-Tooth syndrome, in which both the motor and sensory nerves are affected (Dyck et al. 1993). When only the peripheral motor nervous system is affected, the neuropathy is classified as distal hereditary motor neuropathy (Harding 1993). In contrast, sensory dysfunction prevails in the HSNs. As the autonomic nervous system is involved to a varying degree in HSNs they are often referred to as hereditary sensory and autonomic neuropathies (HSANs) (Dyck 1993).
The HSNs/HSANs are a clinically and genetically heterogeneous group of disorders. Patients usually exhibit prominent distal sensory loss with manifest insensitivity to pain in some. The prominent distal sensory loss frequently leads to chronic ulcerations in feet and hands, sometimes resulting in severe complications such as extensive soft tissue infections, osteomyelitis necessitating amputations of toes and fingers or, in rare instances, even of more proximal parts of the extremities (Dyck 1993). Autonomic dysfunction, such as anhidrosis, fever, blood pressure fluctuations and gastro-intestinal disturbances are present in some patients. Electrophysiologically, axonal nerve damage of sensory neurons is often found, but additional demyelination may also be present (Auer-Grumbach et al. 2003).
HSAN can be transmitted as an autosomal dominant (AD) or autosomal recessive (AR) trait. Isolated patients have also been described (Dyck 1993; Auer-Grumbach 2004). The AD types of HSAN usually present in the second or third decade of life with marked sensory involvement and minimal autonomic and variable motor involvement, while AR HSAN present either as congenital syndromes with striking sensory and autonomic abnormalities or as almost pure autonomic disorders (Verpoorten et al. 2006a).
A classification of the hereditary sensory neuropathies into types HSAN I-V (Dyck, 1993) was made based on age at onset, inheritance pattern and additional features. Molecular genetic research has shown that at least seven genes are associated with the different types of HSNs/HSANs (located on the worldwide web at www.molgen.ua.ac.be/CMTMutations/). Two genes have been associated with AD HSAN: missense mutations in serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) are found in families and individuals with HSAN type I, an adult-onset sensory neuropathy (Bejaoui et al. 2001; Dawkins et al. 2001). Mutations in the small GPTase late endosomal protein RAB7, cause CMT2B (Verhoeven et al. 2003; Meggouh et al. 2006). Mutations in the WNK1/HSN2 gene (protein kinase with-no-lysine(K)-1/hereditary sensory neuropathy type 2) and FAM134B cause AR HSAN type II, an early-onset ulcero-mutilating sensory neuropathy (Lafreniere et al. 2004; Kurth et al. 2009). HSAN type III, also known as Familial Dysautonomia or Riley-Day syndrome, presents with typical prominent autonomic manifestations early in life and is caused by mutations in the inhibitor of kappa-light polypeptide gene enhancer in B cells, kinase complex associated protein (IKBKAP) (Slaugenhaupt et al. 2001). Mutations in neurotrophic tyrosine kinase, receptor type 1 (NTRK1) are reported in families with congenital insensitivity to pain, anhidrosis and mental retardation (CIPA or HSAN type IV) (Indo et al. 1996). HSAN type V, a phenotype closely related to CIPA but with normal mental development and less pronounced anhidrosis, can be caused by mutations in nerve growth factor beta (NGFB) (Einarsdottir et al. 2004) but also by NTRK1-mutations (Houlden et al. 2001; Einarsdottir et al. 2004). Apart from these six HSAN subtypes other forms with distinct additional features exist, e.g., HSAN with gastroesophageal reflux and cough (Kok et al. 2003) and HSAN with spastic paraplegia (Bouhouche et al. 2006b). Recently, the gene for this last form has been identified as cytosolic chaperonin-containing t-complex peptide-1 (CCT5) (Bouhouche et al. 2006a).
The identification of causative genes for the HSAN forms in recent years has provided preliminary insights in the pathogenesis of these rare neuropathies although the fundamental underlying pathomechanisms still remain to be unveiled (Verhoeven et al. 2006). Additional descriptions of HSAN families and patients with known or novel genetic defects are needed to further refine the existing classification and to get a better insight into the molecular basis of these disorders.